The major goal of this project is to develop a non-invasive marker of biological activity of Protein Kinase C (PKC) inhibitors in order to improve treatment with these agents. The PKC pathway is involved in apoptosis and may therefore represent a novel target for anti-cancer therapy. Non-invasive markers of activity of these drugs would be of significant value of optimizing the interaction of PKC inhibitors with chemotherapy agents. Data from both preclinical and clinical studies suggest that the activity of these agents is not solely via inhibition of PKC activity, but may be mediated via vasoconstriction, which would be expected to induce acidosis and reduction in high energy phosphates. We propose to monitor these effects non-invasively by 31P NMR spectroscopy. We hypothesize that activity of PKC inhibitors, and particularly their modulation of the activity of other drugs, may be related to changes in pH and energy and that selecting the interval between drugs on the basis of these metabolic changes will lead to enhanced efficacy. 31P NMR spectroscopy is proposed to study patients receiving treatment in the Phase I and II program of PKC inhibitors (i.e. Bryostatin, flavopiridol, etc) in combination with chemotherapy, and determine if there is a reduction in pH and high energy phosphates after treatment with PKC inhibitors, whether these metabolic changes are related to response and toxicity, and whether these changes correlate with other serum or tissue markers of response. Patients will be studied prior to, and after treatment with different PKC inhibitors, particularly, Bryostatin 1 and flavopiridol, which are undergoing clinical trials. NMR findings will be correlated with response, toxicity and other surrogate markers (serum and biopsy PKC activity, TdT, cdk2, and TNFa). Since this technique is noninvasive, it is an ideal tool for probing changes in cell metabolism in response to these drugs. 3 dimensional chemical shift imaging will be used for signal localization. In addition, 1H spin decoupling will enhance the ability to resolve phophomonesters and phosphodiesters.